SURGICAL THERAPIES
Authors: M. Aghi, M. A. Vogelbaum, D. J. Jolly, J. M. Robbins, D. Ostertag, C. E. Ibanez, H. E. Gruber, N. Kasahara, K. Bankiewicz, T. F. Cloughesy, S. M. Chang, N. Butowski, S. Kesari, C. Chen, T. Mikkelsen, J. Landolfi, E. A. Chiocca, J. B. Elder, G. Foltz, D. Pertschuk, A. Anaizi, C. Taylor, J. Kosty, L. Zimmer, P. Theodosopoulos, A. Anaizi, E. Gantwerker, M. Pensak, P. Theodosopoulos, A. Anaizi, S. Grewal, P. Theodosopoulos, L. Zimmer, A. Anaizi, M. Pensak, P. Theodosopoulos, Y. Arakawa, Y. Kang, D. Murata, K.-i. Fujimoto, S. Miyamoto, M. Blagia, M. Paulis, G. Orunesu, S. Serra, J. Akers, V. Ramakrishnan, R. Kim, J. Skog, I. Nakano, S. Pingle, J. Kalinina, S. Kesari, X. Breakfield, F. Hochberg, E. Van Meir, B. Carter, C. Chen, T. Czech, J. Nicholson, D. Frappaz, R.-D. Kortmann, C. Alapetite, M.-L. Garre, U. Ricardi, F. Saran, G. Calaminus, P. D. W. Hamer, E. Hendriks, E. Mandonnet, F. Barkhof, K. Zwinderman, H. Duffau, Y. Esquenazi, J. Johnson, N. Tandon, Y. Esquenazi, E. Friedman, Y. Lin, J.-J. Zhu, N. Tandon, T. Fujimaki, M. Kobayashi, K. Wakiya, M. Ohta, J. Adachi, K. Fukuoka, T. Suzuki, T. Yanagisawa, M. Matsutani, K. Mishima, J. Sasaki, R. Nishikawa, M. Hoffermann, L. Bruckmann, K. M. Ali, M. Asslaber, F. Payer, G. von Campe, C. Jungk, B. Beigel, V. Abb, C. Herold-Mende, A. Unterberg, J. H. Kim, Y. H. Cho, C. J. Kim, Y. Mardor, O. Nissim, Y. Grober, D. Guez, D. Last, D. Daniels, C. Hoffmann, D. Nass, A. Talianski, R. Spiegelmann, Z. Cohen, L. Zach, N. Marupudi, S. Mittal, K. Michaud, L. Cantin, S. Cottin, C. Dandurand, A. Mohammadi, A. Hawasli, A. Rodriguez, J. Schroeder, A. Laxton, P. Elson, S. Tatter, G. Barnett, E. Leuthardt, S. Moriuchi, M. Dehara, T. Fukunaga, Y. Hagiwara, H. Soda, M. Imakita, M. Nitta, T. Maruyama, H. Iseki, S. Ikuta, M. Tamura, M. Chernov, S. Okamoto, Y. Okada, Y. Muragaki, S. Ohue, S. Kohno, A. Inoue, D. Yamashita, Y. Kumon, T. Ohnishi, P. Oppido, V. Villani, A. Vidiri, A. Pace, A. Pompili, C. Carapella, D. Orringer, D. Lau, Y. Niknafs, J. Piquer, J. L. Llacer, V. Rovira, P. Riesgo, A. Cremades, R. Rotta, N. Levine, S. Prabhu, R. Sawaya, J. Weinberg, G. Rao, S. Tummala, C. Tilley, R. Rovin, A. Kassam, C. Schwartz, A. Romagna, N. Thon, J.-C. Tonn, S. B. Schwarz, F.-W. Kreth, Y. Sonoda, I. Shibahara, R. Saito, M. Kanamori, T. Kumabe, T. Tominaga, C. Steele, J. Lawrence, R. Rovin, R. Winn, W. Rachinger, M. Simon, S. Dutzmann, G. Feigl, N. Kremenevskaya, N. Thon, J.-C. Tonn, H. Whelan, M. Kelly, S. Jogel, B. Kaufmann, A. Foy, S. Lew, B. Quirk, R. L. Yong, T. Wu, N. Mihatov, M. J. Shen, M. A. Brown, K. A. Zaghloul, G. E. Park, J. K. Park
Journal: Neuro-Oncology (2013)

We are conducting investigational dose escalation trials in patients with High Grade Glioma (HGG, NCT01156584 and NCT01470794), using a retroviral replicating vector (Toca 511).Toca 511 (vocimagene amiretrorepvec) encodes an optimized yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-FU in infected tumors.We report here results of a Phase 1/2 trial of direct intratumoral Toca 511 administration to recurrent HGG patients, followed by repeat courses of oral 5-FC.Six Toca 511 dose levels, escalated by half logs, the mode of administration and the use of extended release 5-FC (Toca FC) were investigated in 25 HGG patients to date.Treatment at all dose levels has been well tolerated.Post-treatment resection in two patients showed viral protein and DNA and RNA sequences including the CD gene, suggesting viral spread and persistence.MRI and clinical improvements were also occasionally observed.Virus was initially delivered via a brain biopsy needle and placement in the tumor was predicted using conventional neuro-navigation.Immediate MRI after injection of Toca 511 spiked with gadolinium showed inconsistent delivery of Toca 511 to tumors.As a result, real-time MRI-guided delivery was introduced using Toca 511 infusion with a stepped-tip cannula.Using this approach, delivery into as many as 4 locations of up to 3 mL of Toca 511 at flow rates of up to 30 mL/min has been achieved without reflux.In a tumor biopsy from a patient who received 1 mL of Toca 511 and subsequent Toca FC, we observed tumor selective vector transduction and expression by PCR and RT-PCR with concomitant tumor necrosis.At higher Toca 511 doses, significant MRI changes consistent with tumor regression were observed post-Toca FC dosing.Completion of this study is planned, including dose escalation of Toca 511 and increasing the dose and duration of Toca FC.